Main interests

During ageing and disease cells are exposed to increased levels of stress that damages various biomolecules, including cellular proteins.
Accumulation of damaged or otherwise obsolete proteins is often toxic and can lead or contribute to cell damage during ageing or disease. Thus, it is critical that cells efficiently repair or dispose of such proteins. Elimination of damaged proteins is tightly regulated and involves a variety of proteases and proteolytic systems, including the ubiquitin proteasome system (UPP) and various forms of autophagy.

In the last few years it became apparent that proteolytic systems have unanticipated signalling functions in the cell. For example, targeting of protein substrates by ubiquitin targets not only proteins for proteasomal degradation but it also regulates subcellular trafficking and DNA transcription.
Our group is interested in exploring non-canonical functions for proteolytic signalling and in the putative crosstalk between the various proteolytic systems in the cell. We want to understand how cooperation between proteolytic systems can contribute to the fine-tuning of key regulatory proteins under specific conditions. For instance, we have shown that the HIF-1alpha protein, a transcription factor that helps tissues and organs to cope with hypoxia, can be regulated by a complex cross-talk between UPP and new particular form of autophagy called Chaperon-Mediated Autophagy (CMA).
We have also shown that intercellular communication through gap-junctions can be fine-tuned by a complex molecular interplay involving UPP, autophagy and specific deubiquitinating enzymes that target the Gap-junction protein connexin 43 (Cx43). By pursuing these studies we have identified new targets for CMA and for macroautophagy (such as HIF and Cx43). We have also identified critical molecular players, such as co-chaperone CHIP that mediates triage decisions between the proteolytic systems (UPP and CMA) and protein folding.

In close collaboration with our colleagues at CNC.IBILI we have used various cell and animal models to assess the physiological relevance and pathophysiological implications of the regulation of proteolysis and disruption of proteostasis in health and disease.
For example we have shown that tight regulation of proteostasis and crosstalk between proteolytic systems play key roles in diseases such as Age Related Macular Degeneration, diabetic retinopathy cardiac isquemia, tumour growth etc.

Our goal is to continue to elucidate unanticipated roles for key regulators of the cross-talk between proteolytic systems in the cell, to identify key molecular players and new signalling functions for proteolysis, thus opening new avenues for the understanding and treatment of diseases associated with deregulation of proteostasis, including age-related diseases.